The present invention relates to a novel macrolide compound or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof; a composition comprising the compound and a suitable carrier; a method of preparing the compound; and a method of treatment and prevention of infections in a mammal comprising administering the compound.
Erythromycins A, B, C and D, represented by the formula below,
are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterial agents, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
U.S. Pat. No. 4,874,748 describes a 2-norerythromycin D derivative, which were produced in a strain Streptomyces erythreus 12693-240 transformed by pNJI bearing DNA from Streptomyces antibioticus. The potential of using genetic engineering techniques to produce novel members of the commercially important class of antibiotics, the macrolides, was demonstrated by James B. McAlpine et al., Journal of Antibiotics, XL(8) 1115-1122 (1987). These processes provide structurally determined 2-norerythromycin derivatives, however the antibacterial activities of 2-norerythromycins A, B, C and D can be somewhat disappointing.
PCT Publication No. WO 99/21871, published on May 6, 1999, describes the 2-position of a 3,9-diketo-6xe2x80x94O-substituted tricyclic imine or carbamate can be substituted with a halogen. The C-2 carbon of the 2-substituted 3,9-diketo-6xe2x80x94O-substituted tricyclic imine or carbamate is substituted with a methyl and a halogen atom selected from fluorine, chlorine, bromine or iodine.
Copending U.S. patent application Ser. No. 09/312,517, filed May 14, 1999, discloses C-2 modified erythromycin derivatives wherein the C-2 carbon of a 6xe2x80x94O-substituted ketolide derivative has been substituted with methyl and a substituent selected from substituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl.
U.S. Pat. Nos. 5,561,118; 5,770,579 and 5,444,051 describe erythromycin derivatives having C-2 substitution with methyl and a substituent selected from hydrogen, alkyl and alkylamine.
The invention relates to a new class of macrolide compounds having antibacterial activity. Novel modifications of the C2-position of compounds of the invention provide a new class of 6xe2x80x94O-alkyl-2-nor-2-substituted ketolide derivatives. The compounds can be prepared via C2-derivatization of a 2-norerythromycin fermentation product or the 2-methyl group of an erythromycin derivative can be removed by new methods and further derivatized to afford the desired C2-derivatization. Pharmaceutical compositions and a method of treatment are also described herein.
In one aspect, therefore, the present invention relates to compounds selected from the group consisting of: 
or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, wherein:
Rp is hydrogen or a hydroxy protecting group;
R1 is selected from the group consisting of:
(a) C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of:
(i) hydroxy;
(ii) xe2x80x94CHxe2x95x90O;
(iii) aryl;
(iv) substituted aryl;
(v) heteroaryl;
(vi) substituted heteroaryl;
(vii) Ar1-Ar2, wherein Ar1 and Ar2 are independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
(viii) xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or wherein Rxe2x80x2 and Rxe2x80x3 are taken with nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(C1-C6-alkyl-)xe2x80x94, xe2x80x94N(aryl-C1-C6-alkyl-), xe2x80x94N(substituted aryl-C1-C6-alkyl-)xe2x80x94, xe2x80x94N(heteroaryl-C1-C6-alkyl-)xe2x80x94, and xe2x80x94N(substituted heteroaryl-C1-C6-alkyl-)xe2x80x94;
(b) C1-C6-alkenyl;
(c) C1-C6-alkenyl-R2;
(d) C1-C6-alkynyl; and
(e) C1-C6-alkynyl-R2;
R2 is selected from the group consisting of:
(a) hydrogen;
(b) aryl;
(c) substituted aryl;
(d) heteroaryl;
(e) substituted heteroaryl; and
(f) Ar1-Ar2, wherein Ar1 and Ar2 are as defined above;
R3 is selected from the group consisting of:
(a) hydrogen;
(b) OH;
(c) F, Cl, Br or I;
(d) C1-alkyl substituted with one or more substituents selected from the group consisting of:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 as defined above; and
(vi) xe2x80x94OR5, wherein R5 is hydrogen or C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of:
(1) aryl;
(2) substituted aryl;
(3) heteroaryl; and
(4) substituted heteroaryl;
(vii) xe2x80x94OC(O)R5, wherein R5 is as defined above;
(e) C2-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 as defined above;
(vi) xe2x80x94OR5, wherein R5 is as defined above; and
(vii) xe2x80x94OC(O)R5, wherein R5 is as defined above;
(f) C1-C6-alkenyl;
(g) C1-C6-alkenyl-R2, wherein R2 is as defined above;
(h) C1-C6-alkynyl;
(i) Cxe2x80x94C6-alkynyl-R2, wherein R2 is as defined above;
(j) xe2x80x94OR5, wherein R5 is as defined above;
(k) xe2x80x94OC(O)R5, wherein R5 is as defined above;
(l) xe2x80x94CH2SO2NHR5, wherein R5 is as defined above;
(m) xe2x80x94CH2S(O)xR5, wherein x is 0,1 or 2, and R5 is as defined above; and
(n) xe2x80x94CH2NHR5, wherein R5 is as defined above;
R4 is selected from the group consisting of:
(a) hydrogen;
(b) OH;
(c) NH2;
(d) NHR5, wherein R5 as defined above;
(e) PhSe;
(f) F, Cl, Br or I,
or R3 and R4 taken together with the atoms to which each is attached forms a 3- to 6-membered aromatic or non-aromatic ring optionally containing a heteroatom, wherein the non-aromatic ring optionally contains one to two double bonds or R3 and R4 taken together form a xe2x95x90CH2 (exocyclic methylene), xe2x80x94CH2Oxe2x80x94 (epoxide) or xe2x95x90O (oxo);
Ra, Rb, Rc and Rd are independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6 alkyl, optionally substituted with one or more substituents selected from the group consisting of:
(i) xe2x80x94Lxe2x80x94Mxe2x80x94R6, wherein
L is either absent or selected from the group consisting of:
(1) xe2x80x94C(O)NHxe2x80x94;
(2) xe2x80x94NHC(O)xe2x80x94;
(3) xe2x80x94NHxe2x80x94;
(4) xe2x80x94N(CH3)xe2x80x94;
(5) xe2x80x94Oxe2x80x94;
(6) xe2x80x94S(O)xxe2x80x94, wherein x is 0, 1, or 2;
(7) xe2x80x94C(xe2x95x90NH)NHxe2x80x94;
(8) xe2x80x94NHC(xe2x95x90NH)xe2x80x94;
(9) xe2x80x94C(O)Oxe2x80x94;
(10) xe2x80x94OC(O)xe2x80x94;
(11) xe2x80x94OC(O)NHxe2x80x94;
(12) xe2x80x94NHC(O)Oxe2x80x94; and
(13) xe2x80x94NHC(O)NHxe2x80x94;
M is either absent or selected from the group consisting of:
(1) xe2x80x94(CH2)1xe2x80x94, wherein 1 is 1 to 5,
(2) xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94, wherein m is 0 to 3,
(3) xe2x80x94(CH2)nxe2x80x94Cxe2x89xa1Cxe2x80x94 wherein n is 0 to 3;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) aryl,
(3) substituted aryl,
(4) heteroaryl,
(5) substituted heteroaryl, and
(6) Ar1-Ar2, wherein Ar1 and Ar2 are independently selected from the group consisting of:
(a) aryl,
(b) substituted aryl,
(c) heteroaryl, and
(d) substituted heteroaryl; and
(ii) halogen;
(c) C3-C7 cycloalkyl;
(d) heterocycloalkyl; and
(e) substituted heterocycloalkyl;
or any one pair of substituents selected from the group consisting of RaRb, RaRc, RaRd, RbRc, RbRd, and RcRd taken together with the atom or atoms to which they are attached form a 3- to 7-membered ring optionally containing a hetero function selected from the group consisting of xe2x80x94Oxe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94N(C1-C6 alkyl-)xe2x80x94; xe2x80x94N(aryl-C1-C6 alkyl-)xe2x80x94; xe2x80x94N(substituted aryl-C1-C6 alkyl-)xe2x80x94; xe2x80x94N(heteroaryl-C1-C6 alkyl-)xe2x80x94; xe2x80x94N(substituted heteroaryl-C1-C6 alkyl-)xe2x80x94; xe2x80x94S(O)xxe2x80x94, wherein x is as defined above; xe2x80x94C(O)xe2x80x94NHxe2x80x94; xe2x80x94NHxe2x80x94C(O)xe2x80x94; xe2x80x94C(O)xe2x80x94NRxe2x80x94; and xe2x80x94NR12xe2x80x94C(O)xe2x80x94; wherein R12 is hydrogen, C1-C3 alkyl, C1-C3 alkyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and
Y is selected from the group consisting of:
(a) hydrogen,
(b) NH2;
(c) OH;
(d) Zxe2x80x94R7, wherein Z is selected from the group consisting of:
(i) xe2x80x94NHxe2x80x94(CH2)pxe2x80x94, wherein p is 0 to 5;
(ii) xe2x80x94(CH2)pxe2x80x94, wherein p is as defined above;
(iii) xe2x80x94NHxe2x80x94C1-C5 alkene-;
(iv)-C1-C5 alkene-;
(v) xe2x80x94NHxe2x80x94C1-C5 alkyn-, and
(vi) xe2x80x94C1-C5 alkyn-; and
xe2x80x83R7 is selected from the group consisting of:
(i) hydrogen;
(ii) aryl; (iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl, and
(vi) Ar1-Ar2, wherein Ar1 and Ar2 are as defined above.
In another aspect, the invention relates to a process for preparing a compound of formula (I) or (II) comprising the steps of:
(a) treating a compound of the formula: 
xe2x80x83wherein Rp and Rp2 are independently selected from the group consisting of hydrogen and a hydroxy protecting group, under suitable conditions for:
(i) protecting the 2xe2x80x2- and optionally the 4xe2x80x3-hydroxy groups;
(ii) converting the C9-carbonyl into a C9-oxime;
(iii) alkylating the 6xe2x80x94O-hydroxy; (iv) optionally deprotecting the 2xe2x80x2- and 4xe2x80x3-hydroxy groups;
(v) deoximating the C9-oxime;
(vi) removing the 3-cladinose sugar and oxidizing the resulting 3-hydroxy group; and
(vii) preparing a 10,11-anhydro-12-acylimidazolyl derivative of the compound
to afford a compound of the formula: 
(b) treating the compound obtain in step (a) with ammonia, ammonia hydroxide, a primary amine of the formula Yxe2x80x2xe2x80x94NH2, wherein Yxe2x80x2 is Zxe2x80x94R7 and Z and R7 are as defined above, or a diamine of the formula: 
xe2x80x83wherein Ra, Rb, Rc and Rd are as defined above, to provide a compound of the formula: 
xe2x80x83wherein Y, R1, Ra, Rb, Rc, Rd, and Rp are as previously defined;
(c) derivatizing the C2-position of a compound of formula (V) or (VI) in one of the following manners:
(i) alkylation with a C, N, S, or O electrophile;
(ii) oxidation of a compound obtained from step (c)(i);
(iii) alkylation of a compound obtained from step (c)(i);
(iv) treating the compound obtained in step (c)(ii) with a carbon, nitrogen, sulfur, or oxygen nucleophile; and
(v) replacing one or both C2-hydrogen atoms with a halogen atom; and
(d) optionally removing any hydroxy protecting group that may be present.
In another aspect, the invention relates to a process for preparing a compound of formula (I) or (II), as defined above, comprising the steps of:
(a) treating a compound of the formula: 
xe2x80x83wherein Y, R1, Ra, Rb, Rc, Rd and Rp are as previously defined, with a suitable electrophilic reagent in the presence of base to obtain a compound of the formula: 
xe2x80x83wherein Re is a C2-leaving group selected from the group consisting of hydroxy, halide, sulfone, sulfoxide, sulfide and selenide;
(b) oxidizing the C2-position of a compound in step (a), as necessary, and eliminating the C2-leaving group optionally in the presence of a base to provide a suitable C2-exocyclic methylene group;
(c) derivatizing the C2-position in one of the following manners:
(i) oxidizing the C2-exocylic methylene of the compound obtained in step (b) followed by reacting with a carbon, nitrogen, sulfur, or oxygen nucleophile;
(ii) treating the compound obtained in step (b) with a carbon, nitrogen, sulfur or oxygen nucleophile; and
(iii) hydrolyzing the compound obtained in step (b) under basic conditions followed by alkylation, oxidation or halogenation; and
(d) optionally removing any hydroxy protecting group that may be present.
In yet another aspect, the invention relates to a pharmaceutical composition comprising a compound as described above and a pharmaceutically acceptable carrier.
Yet another aspect of the invention relates to a method of treating a bacterial infection comprising administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment.
The term xe2x80x9cC1-C6 alkylxe2x80x9d as used herein refers to saturated, straight, or branched chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and six carbon atoms by removal of a single hydrogen atom. In general, a group denoted as Cx-Cy, wherein x and y are integers, refers to a group of x to y carbon atoms. For example, the group Cx-Cy alkyl, wherein x is 1 and y is 3, includes C1-C3 alkyl radicals such as methyl, ethyl, propyl, and isopropyl. Exemplary C1-C6 alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl. Examples of C1-C12 alkyl radicals include all the foregoing examples, as well as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-docecyl.
The term xe2x80x9cC1-C6 alkenylxe2x80x9d as used herein refers to straight- or branched-chain hydrocarbon radicals comprising one to six carbon atoms, respectively, which contain one or more carbonxe2x80x94carbon double bonds. Compounds of the invention have either a known configuration or exist as a mixture of isomers.
The term xe2x80x9cC1-C6 alkynylxe2x80x9d used herein refers to straight- or branched-chain hydrocarbon radicals comprising one to six carbon atoms, respectively, which contain one or more carbonxe2x80x94carbon triple bonds. Compounds of the invention have either a known configuration or exist as a mixture of isomers.
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono-, fused bicyclic or fused tricyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, anthracenyl, phenanthrenyl, biphenylenyl, fluorenyl, and the like.
The term xe2x80x9csubstituted arylxe2x80x9d as used herein refers to an aryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group. Substituents also include alkenyloxy, for example, methylenedioxy and ethylenedioxy. The substituted aryl groups also include tetrafluorophenyl and pentafluorophenyl.
The terms xe2x80x9chaloxe2x80x9d, xe2x80x9chalidexe2x80x9d, and xe2x80x9chalogenxe2x80x9d as used herein refer to an atom selected from fluorine, chlorine, bromine, and iodine.
The term xe2x80x9cheteroarylxe2x80x9d as used herein refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; one, two, or three ring atoms may be additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiophenyl, furanyl, quinolinyl, quinoxalinyl, isoquinolinyl, and the like.
The term xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocyclexe2x80x9d, and xe2x80x9cheterocycloalkylxe2x80x9d as used herein refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered ring system which includes single rings of 3 to 8 atoms in size and bi- or tricyclic ring systems which may include aromatic six-membered aryl or heteroaryl rings fused to a non-aromatic ring. These heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
Representative heterocycles include pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
The term xe2x80x9csubstituted heteroarylxe2x80x9d as used herein refers to a heteroaryl group as defined above substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, cyano, C1-C3 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted with aryl, haloalkyl, thioalkoxy, alkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, mercapto, xe2x80x94SO3H, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, arylalkyl, cycloalkyl, heteroaryl, or heterocycloalkyl group.
The term xe2x80x9csubstituted heterocycloalkylxe2x80x9d as used herein, refers to a heterocycloalkyl group, as defined above, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, cyano, C1-C3 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group.
The term xe2x80x9chydroxy protecting groupxe2x80x9d as used herein refers to an easily removable group to which are known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, c.f., for example T. H. Wiley and Sons, New York (1991). Examplary hydroxy protecting groups are methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acyl substituted with an aromatic group, and the like.
The term xe2x80x9cprotected hydroxyxe2x80x9d as used herein refers to a hydroxy group protected with a hydroxy protecting group as defined above including, but not limited to, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl, and the like.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein refers to those carboxylate salts, esters, and prodrugs of the compound of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Pharmaceutically acceptable salts are well known in the art and refer to the relatively non-toxic, inorganic and organic acid addition salts of the compound of the present invention. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), which is incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
As used herein, the term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term xe2x80x9cpharmaceutically acceptable solvatexe2x80x9d represents an aggregate that comprises one to three molecules of the solute, such as a compound of the invention, with one, two, or three molecules of solvent. Suitable pharmaceutically acceptable solvates include hydrates, wherein the solute is one, two or three molecules of water, and those solvates wherein the solute is a solvent which is suitable for use in a pharmaceutical product, such as ethanol.
The term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Numerous asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof.
A preferred compound of the invention is represented by the formula: 
wherein Y, R2, R3, R4, and Rp are as previously defined.
Another preferred compound of the invention is represented by the formula: 
wherein Y, R2, R3, R4 and Rp are as previously defined.
Yet another preferred compound of the invention is represented by the formula: 
wherein R2, R3, R4, Ra, Rb, Rc, Rd, and Rp, are as previously defined.
Still yet another preferred compound of the invention is represented by the formula: 
wherein R2, R3, R4, Ra, Rb, Rc, Rd, and Rp, are as previously defined.
Representative compounds of the invention include, but are not limited to the following:
Compound of formula (XI), Rp is benzoyl, Y is Hydrogen, R2 is 3-quinolyl, R3 and R4 taken together is xe2x95x90CH2;
Compound of formula (XI), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 is hydrogen and R4 is hydrogen;
Compound of formula (I), Rp is hydrogen, Y is hydrogen, R1 is xe2x80x94CH2CH(OH)CH(OH)xe2x80x94(3-quinolyl), R3 is xe2x80x94CH2O H and R4 is OH;
Compound of formula (I), Rp is hydrogen, Y is hydrogen, R1 is xe2x80x94CH2CHxe2x95x90O, R3 is xe2x80x94CH2O H and R4 is OH;
Compound of formula (XI), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 is xe2x80x94CH2CHxe2x95x90CH2 and R4 is hydrogen;
Compound of formula (XI), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 is xe2x80x94CH2SO3H and R4 is hydrogen;
Compound of formula (XI), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 is xe2x80x94CH2CH(CO2Me)2 and R4 is hydrogen;
Compound of formula (XI), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 and R4 taken together is xe2x80x94CH2Oxe2x80x94;
Compound of formula (XI), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 is F and R4 is hydrogen;
Compound of formula (XI), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 is F and R4 is F;
Compound of formula (XI), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 is xe2x80x94CH2F and R is F;
Compound of formula (XI), Rp is hydrogen, Y is hydrogen, R2 is hydrogen, R3 is hydrogen and R4 is hydrogen;
Compound of formula (XII), Rp is hydrogen, Y is hydrogen, R2 is hydrogen, R3 is hydroxy and R4 is hydrogen;
Compound of formula (XII), Rp is hydrogen, Y is hydrogen, R2 is hydrogen, R3 is hydrogen and R4 is hydrogen;
Compound of formula (XIII), Rp is hydrogen, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen and Rd is hydrogen;
Compound of formula (XIV), Rp is hydrogen, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen and Rd is hydrogen;
Compound of formula (XII), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 is hydrogen and R4 is hydrogen;
Compound of formula (XIII), Rp is Hydrogen, R2 is 3-quinolyl, R3 is hydrogen, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen and Rd is hydrogen;
Compound of formula (XIV), Rp is Hydrogen, R2 is 3-quinolyl, R3 is hydrogen, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen and R is hydrogen;
Compound of formula (XI), Rp is hydrogen, Y is hydrogen, R2 is hydrogen, R3 is F and R4 is hydrogen;
Compound of formula (XII), Rp is hydrogen, Y is hydrogen, R2 is hydrogen, R3 is F and R4 is hydrogen;
Compound of formula (XIII), Rp is hydrogen, R2 is hydrogen, R3 is F, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen and Rd is hydrogen;
Compound of formula (XIV), Rp is hydrogen, R2 is hydrogen, R3 is F, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen and Rd is hydrogen;
Compound of formula (XI), Rp is hydrogen, Y is hydrogen, R2 is hydrogen, R3 is F and R4 is F;
Compound of formula (XII), Rp is hydrogen, Y is hydrogen, R2 is hydrogen, R3 is F and R4 is F;
Compound of formula (XIII), Rp is hydrogen, R2 is hydrogen, R3 is F, R is F, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (XIV), Rp is hydrogen, R2 is hydrogen, R3 is F, R4 is F, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (XI), Rp is hydrogen, Y is hydrogen, R2 is 8-quinoxaline, R3 is F and R4 is hydrogen;
Compound of formula (XII), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 is F and R4 is hydrogen;
Compound of formula (XIII), Rp is Hydrogen, R2 is 3-quinolyl, R3 is F, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (XIV), Rp is Hydrogen, R2 is 3-quinolyl, R3 is F, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (XI), Rp is hydrogen, Y is hydrogen, R2 is 8-quinoxaline, R3 is F and R4 is F;
Compound of formula (XII), Rp is hydrogen, Y is Hydrogen, R2 is 3-quinolyl, R3 is F and R4 is F;
Compound of formula (XIII), Rp is Hydrogen, R2 is 3-quinolyl, R3 is F, R4 is F, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (XIV), Rp is Hydrogen, R2 is 3-quinolyl, R3 is F, R4 is F, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (I), Rp is hydrogen, Y is hydrogen, R1 is methyl, R3 is hydrogen and R4 is hydrogen;
Compound of formula (II), Rp is hydrogen, R1 is methyl, R3 is hydrogen, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (I), Rp is hydrogen, Y is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x95x90CH2 and R4 is hydrogen;
Compound of formula (I), Rp is hydrogen, Y is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x89xa1CH and R4 is hydrogen;
Compound of formula (II), Rp is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x95x90CH2, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (II), Rp is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x89xa1CH, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (II), Rp is hydrogen, Y is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x95x90CHxe2x80x94(3-quinolyl) and R4 is hydrogen;
Compound of formula (I), Rp is hydrogen, Y is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x89xa1Cxe2x80x94(3-quinolyl) and R4 is hydrogen;
Compound of formula (II), Rp is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x95x90CHxe2x80x94(3-quinolyl), R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (II), Rp is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x89xa1Cxe2x80x94(3-quinolyl), R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen, and Rd is hydrogen;
Compound of formula (I), Rp is hydrogen, Y is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x95x90CH2 and R4 is F;
Compound of formula (I), Rp is hydrogen, Y is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x89xa1CH and R4 is F;
Compound of formula (II), Rp is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x95x90CH2, R4 is F, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen and Rd is hydrogen;
Compound of formula (II), Rp is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x89xa1CH, R4 is hydrogen, Ra is hydrogen, Rb is hydrogen, Rc is hydrogen and Rd is hydrogen;
Compound of formula (I), Rp is hydrogen, Y is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x95x90CHxe2x80x94(3-quinolyl), and R4 is F;
Compound of formula (I), Rp is hydrogen, Y is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x89xa1Cxe2x80x94(3-quinolyl), and R4 is F;
Compound of formula (II), Rp is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x95x90CHxe2x80x94(3-quinolyl), R4 is F, Ra is hydrogen, Rc is hydrogen, Rc is hydrogen and Rd is hydrogen; and
Compound of formula (II), Rp is hydrogen, R1 is methyl, R3 is xe2x80x94CH2Cxe2x89xa1Cxe2x80x94(3-quinolyl), R4 is F, Rais hydrogen, Kb is hydrogen, Rc is hydrogen and Rd is hydrogen.
The representative compounds can be prepared from a method as previously described, allowing for minor modification of the reagents and conditions to obtain a desired compound named above. A compound of the invention can be isolated and purified by methods known in the art and provide suitable compounds for a composition of the invention.
Pharmaceutical Compositions
The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer""s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agarxe2x80x94agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation and ear drops are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
According to the methods of treatment of the present invention, bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
The total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more, such as from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of a compounds of the invention per day in a single or multiple doses.
Abbreviations
Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: tBuOH for t-butyl alcohol; CDI for carbonyldiimidazole; CuBr.DMS for copper(I) bromide-dimethylsulfide complex; m-CPBA for m-chloroperbenzoic acid, DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DMSO for dimethyl sulfoxide; EtOAc for ethyl acetate; DMF for dimethylformamide; KOtBu for potassium t-butoxide; MeOH for methanol; NaH for sodium hydride; NCS for N-chlorosuccinimide; NMO for N-methylmorpholine-N-oxide; Me2S for dimethyl sulfide; Ph for phenyl; Pd(PPh3)2Cl2 for dipalladium(triphenylphosphine) dichloride; PhSeCl for phenylselenyl chloride; (PhSO2)2NF for N-fluorobenzenesulfonimide; TEA for triethylamine; THF for tetrahydrofuran; and TPP for triphenylphosphine. Starting materials, reagents, and solvents are available from Aldrich Chemical Company (Milwaukee, Wiss.) unless otherwise noted herein.
Synthetic Methods
The compounds and processes of the present invention will be better understood in connection with the following synthetic Schemes, which illustrate the methods by which the compounds of the invention may be prepared. The compounds of general formula (I) and (II) may be prepared by derivatizing a 2-nor-6xe2x80x94O-substituted ketolide compound or derivative thereof prepared from a 2-nor erythromycin fermentation product or, alternatively, by chemically modifying the C2-position of a suitable 6xe2x80x94O-substituted ketolide obtained from erythromycin A or a derivative thereof.
A 2-nor-6xe2x80x94O-ketolide substrate can be prepared from a 2-norerythromycin A (available from Abbott Laboratories, Abbott Park, Ill.), which is obtained by fermentation techniques. The 2-nor derivatives of erythromycin A, B, C and D were produced in a strain Streptomyces erythreus 12693-240 (NRRL B-1 8053) transformed by pNHI bearing DNA (NRRL B-1 8054) from Streptomyces antibioticus. Macrolide 2-norerythromycin compounds have been identified from the fermentation medium of S. erythreus 12693-240. A subculture of this microorganism was deposited in the permanent collection of the National Center for Agricultural Utilization Research, United States Department of Agriculture, 1815 North University Street, Peoria, Ill. 61604, U.S.A., and accorded accession number NRRL B-18055.
To obtain the 2-norerythromycin compounds, Streptomyces erythreus strain NRRL 12693-240 was innoculated into 500 ml of SCM medium (1.5% soluble starch, thiostrepton at 2 xcexcg/ml) and grown for 3-6 days at 32xc2x0 C. The entire culture was then innoculated into 10 liters of fresh SCM medium containing thiostrepton at 2 xcexcg/ml and 5% soy bean oil and fermented for a period of 7 days at 32xc2x0 C. The fermentation medium was sequentially extracted with ethyl acetate to obtain the antibiotic-containing fractions. Methods for preparing 2-norerythromycin A, B, C or D are described in U.S. Pat. No. 4,874,748, the disclosure of which is incorporated herein.
The 2-norerythromycin compounds can be treated in accordance with reaction conditions for the protection, oximation, alkylation, deprotection, deoximation, removal of the cladinose sugar (descladinozation), oxidation and acylation reactions described in the art to obtain a 10,11-anhydro-12-acylimidazolyl erythromycin A derivative, which can be transformed into a suitable substrate for C2-derivatization. In a preferred process, an 11,12-carbamate derivative or a tricyclic imine derivative is prepared from the 10,11-anhydro-12-acylimidazolyl ketolide intermediate. An example of a procedure suitable for preparing the 6xe2x80x94O-substituted ketolide substrate is shown below in Scheme 1. 
As shown in Scheme 1, conversion of 2-norerythroycin A to a compound 1a can be carried out using methods for converting a 9-oxime erythromycin derivative. The C9-carbonyl group of the 2-norerythromycin A is typically protected as an oxime, wherein V is Nxe2x80x94Oxe2x80x94(CH2)sxe2x80x94Rx, Nxe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)sxe2x80x94Rx, or Nxe2x80x94Oxe2x80x94C(Ry)(Rz)-Oxe2x80x94(CH2)sxe2x80x94Rx, wherein s is 0 to 5 and Rx is (a) hydrogen, (b) alkyl (c) substituted alkyl (d) aryl, (e) substituted aryl, (f) heteroaryl, and (g) substituted heteroaryl, and wherein Ry and Rz are independently selected from (a) hydrogen, (b) unsubstituted C1-C12-alkyl, (c) C1-C12-alkyl substituted with aryl, and (d) C1-C12-alkyl substituted with substituted aryl, or Ry and Rz taken together with the carbon to which they are attached form a C3-C12-cycloalkyl ring. A preferred protected oxime group V is Nxe2x80x94Oxe2x80x94(1-isopropoxycyclohexyl) or Nxe2x80x94Oxe2x80x94C(O)-phenyl (i.e. Nxe2x80x94O-benzoyl). Conditions for the protection of the 9-oxime of erythromycin derivatives are further described in U.S. Pat. Nos. 4,990,602; 4,331,803, 4,680,368; and 4,670,549; and European Patent Application EP 260,938, the disclosures of which are herein incorporated by reference.
The 2xe2x80x2- and optionally the 4xe2x80x3-hydroxy groups of the erythromycin A can be treated with a suitable hydroxy protecting reagent in an aprotic solvent. Hydroxy protecting reagents include, for example, acetic anhydride, benzoic anhydride, hexamethyldisilazane, or a trialkylsilyl chloride in an aprotic solvent. Examples of aprotic solvents are dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone, dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. Aprotic solvents do not adversely affect the reaction, and are preferably dichloromethane, chloroform, DMF, tetrahydrofuran, N-methyl pyrrolidinone or a mixture thereof. The protection of the 2xe2x80x2- and optionally the 4xe2x80x3-hydroxy groups of the C9-protected erythromycin A may be accomplished sequentially or simultaneously. The variables Rp and Rp2 denote hydrogen or a hydroxy protecting group when used throughout the specification in the structural formulas. Preferred protecting groups include, but are not limited to, acetyl, trimethylsilyl, and benzoyl. A thorough discussion of protecting groups and the solvents in which they are most effective is provided by T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Son, Inc., 1991.
Alkylation of the 6xe2x80x94O-hydroxy group of 1a can be accomplished with an alkylating agent in the presence of base to obtain 1b. Suitable alkylating agents include alkyl chlorides, bromides, iodides or alkyl sulfonates. Specific examples of other alkylating agents are allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, xcex1-bromo-p-tolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1-propenyl phenyl sulfone, 3-bromo-1-trimethylsilyl-1-propyne, 1-bromo-2-octyne, 1-bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromochloromethane, bromomethyl phenyl sulfone, and 1,3-dibromo-1-propene. Examples of alkyl sulfonates are allyl tosylate, 3-phenylpropyl trifluoromethane sulfonate, and n-butylmethanesulfonate. Examples of the solvents used are aprotic solvents such as DMSO, diethylsulfoxide, N,N-dimethylformamide, NN-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, mixtures thereof or mixtures of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, or acetone. Examples of the base which can be used are potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, and alkali metal alkoxides such as potassium isopropoxide, potassium tert-butoxide, and potassium iso-butoxide. An especially preferred method of carrying out the alkylation is treatment of 1a with allyl bromide or propargyl bromide in a DMSO/THF mixture with potassium hydroxide or potassium t-butoxide as the base.
Deprotection of the C9-oxime of 1b, wherein V is a protected oxime, can be accomplished under neutral, acidic or basic conditions. Exemplary conditions for deprotecting a protected oxime of the formula Nxe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)sxe2x80x94Rx include, but are not limited to, treatment with an alcoholic solvent at room temperature or at reflux. Preferably, the 9-oxime is deprotected in this manner when Rp is an ester, such as acetate or benzoate. Alcoholic solvents preferred for the deprotection are methanol or ethanol. Exemplary conditions for converting the protected oxime Nxe2x80x94Oxe2x80x94C(Ry)(Rz)xe2x80x94Oxe2x80x94Rx, wherein Rx, Ry, and Rz are as previously described, to the oxime (Nxe2x80x94OH) involve treating compound 1b with aqueous acid in acetonitrile. Aqueous acids suitable for the reaction include, but are not limited to, aqueous acetic acid, hydrochloric acid, and sulfuric acid. During the deprotection of the oxime, the 2xe2x80x2- and 4xe2x80x3-hydroxy protecting groups (Rp and Rp2) can be removed in the process. A thorough discussion of the procedures, reagents and conditions for removing protecting groups is discussed by T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Son, Inc., (1991), which is herein incorporated by reference.
The deoximation reaction can be carried out by reacting the deprotected C9-oxime of 1b, with an inorganic sulfur oxide or an inorganic nitrite salt in a protic solvent. Exemplary inorganic sulfur oxide compounds are sodium hydrogen sulfite, sodium thiosulfate, sodium sulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate, potassium metabisulfite, and the like. Suitable inorganic nitrite salts include, for example, sodium nitrite or potassium nitrite, and the like. Examples of the solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol, or a mixture of one or more of the mentioned solvents, and the like. The reaction is optionally carried out in the presence of an organic acid, such as formic acid, acetic acid and trifluoroacetic acid. Hydrochloric acid is also suitable for the reaction. The amount of acid used is from about 1 to about 10 equivalents of the amount of compound 1b. In a preferred embodiment, the reaction of compound 1b is carried out using sodium nitrite and HCl in ethanol and water to give compound 1c.
The cladinose moiety of compound 1c is removed by mild aqueous acid hydrolysis to give 1d. Representative acids include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid. Suitable solvents for the reaction include methanol, ethanol, isopropanol, butanol and the like. Reaction times are typically 0.5 to 24 hours. The reaction temperature is preferably xe2x88x9210xc2x0 C. to 70xc2x0 C.
The 2xe2x80x2-hydroxy group of the macrolide is optionally protected as previously described using a hydroxy protecting reagent in an aprotic solvent. Preferred hydroxy protecting reagents are acetic anhydride, benzoyl anhydride, or trialkylsilyl chloride. Preferably, the aprotic solvent is dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. A particularly preferred protecting group for the 2xe2x80x2-position (RP) is acetate or benzoate. Protection of the hydroxy group can be accomplished before or after the descladinozation reaction.
The 3-hydroxy group of 1d is oxidized to the ketone 1e using a modified Swern oxidation procedure or Corey-Kim oxidation conditions. Suitable oxidizing agents are N-chloro-succinimide-dimethyl sulfide or carbodiimide-dimethylsulfoxide. In a typical example, 1d is added into a pre-formed N-chlorosuccinimide and dimethyl sulfide complex in a chlorinated solvent, such as methylene chloride, at xe2x88x9220 to 25xc2x0 C. After stirring for 0.5-4 hours, a tertiary amine, such as triethylamine or diisopropylethylamine (Hunig""s base), is added to produce the corresponding ketone.
The 11,12-diol group of 1e can be further treated to obtain an 10,11 -anhydro-12-imidazolyl intermediate compound (IV), which can be converted into an 11,12-carbamate of formula (V) or the tricyclic imine (VI). The intermediate compound of formula (IV) may be prepared from compound 1e by treatment of the latter under anhydrous conditions with an alkali metal hydride or bis(trimethylsilyl) amide in the presence of carbonyldiimidazole in an aprotic solvent. Suitable aprotic solvents are those previously defined. Exemplary reagents can be sodium hydride, lithium hydride, sodium hexamethyldisilazide, lithium hexamethyldisilazide, and the like. Preferably, the solvent is tetrahydrofuran, dimethylformamide, or a mixture thereof. The reaction may require cooling or heating, depending upon the conditions used. The reaction temperature may be from xe2x88x9220xc2x0 C. to 70xc2x0 C., and preferably from 0xc2x0 C. to room temperature. The reaction may require 0.5 hours to 10 days, and is preferably accomplished in 1 to 5 days.
Alternatively, compound 1e is treated with an alkali metal hydride and a phosgene reagent under anhydrous conditions, followed by a base catalyzed decarboxylation, or can be treated with methanesulfonic anhydride in pyridine, followed by treatment with an amine base to provide a suitable anhydro intermediate for treatment with the alkali metal hydride base and carbonyldiimidazole to give compound (IV) in a stepwise manner. Preferably, the phosgene reagent is phosgene, diphosgene, or triphosgene.
To obtain compounds of formula (V), wherein Y is as previously defined, compound (IV) is reacted with a primary amine g of the formula Yxe2x80x2xe2x80x94NH2, wherein Yxe2x80x2 is Zxe2x80x94R7 and Z and R7 are as previously defined. The reaction is carried out in a suitable solvent from room temperature to reflux temperature for about 1 to about 10 days. Exemplary solvents are acetonitrile, tetrahydrofuran, dimethyl formamide, dimethylsulfoxide, dimethyl ether, N-methyl pyrrolidinone, water, or a mixture thereof. Preferred solvents are aqueous acetonitrile, and aqueous DMF.
The compound of formula (V), wherein Y corresponds to hydrogen, can be prepared by reacting a compound of formula (IV) with aqueous ammonia hydroxide or anhydrous ammonia, preferably in acetonitrile, under the conditions as described above for the primary amine.
The prepared 11,12-carbamate derivatives are optionally deprotected. When the protecting group is an ester, the protecting group may be removed by treatment with an organic alcohol, such as methanol or ethanol. Exemplary esters which can be deprotected by treating the ketolide derivatives with an organic alcohol are acetate, benzoate, and the like. When the protecting group is a trialkylsilyl group, deprotection by treatment with fluoride in a polar organic solvent, such as THF or acetonitrile, or aqueous acid hydrolysis is preferred.
Compound (IV) can be reacted with a diamine compound i, wherein Ra, Rb, Rc and Rd are as previously defined, in a suitable polar organic solvent to obtain a corresponding bicyclic amine compound 1j. The diamines for the synthesis can be purchased or prepared by means well known in the art. The compounds have the substituents Ra, Rb, Rc and Rd in accordance with the desired substituents and chirality of the starting material.
Exemplary solvents for the reaction are selected from the group consisting of aqueous acetonitrile, DMF, aqueous DMF, and the like. One amino group of the diamine reagent can be optionally protected to differentiate the two diamine and deprotected prior to cyclization.
Cyclization of the bicyclic amine 1j by treatment with dilute acid in a suitable organic solvent affords the tricyclic derivatives of the invention. The reaction can be accomplished in a period of from about 1 to 10 days at temperatures from about room temperature to reflux. Exemplary acids are acetic acid or HCl. A suitable organic solvent is an alcoholic solvent, such as methanol, ethanol, propanol, and the like, or non polar solvent, such as benzene or toluene.
Optional deprotection of the compound obtained therefrom affords a tricyclic ketolide derivative (VI).
The 2-position of (V) or (VI) can be optionally derivatized to obtain a 2-nor-2-substituted 6xe2x80x94O-alkyl ketolide derivative.
In another method, a 6-O-alkylated ketolide substrate can be prepared from erythromycin A (available from Abbott Laboratories, Abbott Park, Ill.), in accordance with methods readily available to one of skill in the art and the C2-position can be suitably modified to provide a 2-nor-6-O-alkylated ketolide substrate, which can be further derivatized.
Erythromycin A can be treated in accordance with the reaction conditions previously described for the protection, deprotection, alkylation, deoximation, removal of the cladinose sugar (descladinozation), oxidation, and acylation reactions of the 2-norerythromycin A substrate. Exemplary techniques for preparing the 6xe2x80x94O-substituted ketolide are disclosed in U.S. Pat. No. 5,866,549 and PCT Publication No. WO 99/21871, which are herein incorporated by reference. An example of a method for obtaining a 6-O-alkylated ketolide is described in Scheme 2. 
As illustrated in Scheme 2, the 2xe2x80x2-hydroxy, optionally the 4xe2x80x3-hydroxy, and the C9-oxime of the erythromycin derivative are protected to obtain 2a, wherein V, Rp and Rp2 are as previously defined for the 2-norerythromycin substrate. Alkylation of 2a affords the 6-O -alkylated erythromycin derivative 2b, wherein R1 is as previously defined. The intermediate 2b can be deoximated and optionally deprotected to give 2c. Removal of the cladinose sugar of 2c affords compound 2d. Oxidation of the resulting 3-hydroxy moiety of 2d yields a 6xe2x80x94O-alkyl ketolide derivative 2e. The compound 2e can be treated to obtain the 10,11-anhydro-12-imidazolyl compound 2f. The intermediate 2f can be converted to the 11,12-carbamate (VII) or the tricyclic imine (VIII), wherein Y, Ra, Rb, Rc and Rd are as previously defined. Compounds (VII) and (VIII) can be further derivatized by the methods described below to obtain compounds of formula (I) or (II).
Removal of the C2-methyl can be accomplished on the 6xe2x80x94O-alkyl ketolide derivatives (VII) or (VIII). An example of a procedure suitable for removing the methyl group from the 2-position is described below in Scheme 3. 
In accordance with Scheme 3, ketolide (VII) is treated with an electrophilic reagent to obtain intermediate 3, wherein Re is hydroxy, halide, sulfone, sulfoxide, sulfide, or selenide. In a preferred compound 3, Re is halide, phenyl sulfonyl, phenyl sulfoxide, phenyl sulfide or phenyl selenide.
Suitable reagents for providing a halide leaving group include, but are not limited to, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, bromine, chlorine, iodine, and the like. Reagents that allow for the introduction of sulfur leaving groups, wherein Re is sulfone, sulfoxide, or sulfide, are arylsulfonyl halides, arylsulfinic anhydride and aryl disulfides. Exemplary electrophilic sulfur reagents include, but are not limited to, phenylsulfonyl chloride, diphenyl disulfide, and the like. Likewise, for the introduction of selenium electrophiles, areneselenyl halides and diselenyl compounds, for example phenylselenyl chloride, diphenyl diselenide, can be used for the preparation of 3. The preferred reagent is phenylselenyl chloride.
Elimination of the C2-electrophile of 3 to give 4 can be accomplished in the following steps depending on the type of Re. When Re is a halide, arylsulfoxide or arylsuphonyl, the elimination can be affected with the treatment of an amine base, for example 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or Hunig""s base, or with an hydroxy or alkoxy base. Suitable bases for the reaction are potassium hydroxide, tetraalkyl ammonium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium trimethylsilyoxide, and the like.
The elimination of the intermediate wherein R1 is an aryl sulfoxide can be carried out via a thermal elimination upon heating the reaction mixture to 70-150xc2x0 C. When Re is an aryl sulfide, the sulfide is oxidized to a sulfoxide and the sulfoxide leaving group is eliminated by the method described above. The selenide, for example wherein Re is an aryl selenide, can be oxidized to a selenoxide, which spontaneously eliminates at room temperature to give compound 4.
The oxidation of the selenide or sulfide can be carried out using a monopersulfate reagent or a perbenzoic acid in an organic solvent. Exemplary organic solvents are dimethylformamide, dimethyl sulfoxide, dimethoxyethane, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, methanol, ethanol, and the like, or mixtures thereof. Portions of water can be added to obtain an aqueous solution when a monopersulfate reagent is employed. Preferably, the solution is from about 40% to about 60% aqueous. The reaction can be accomplished with from about 1 to about 4 molar equivalents of the monopersulfate compound for each equivalent of ketolide 3. A preferred monopersulfate compound is commercially available as OXONE(copyright) (potassium peroxymonosulfate, DuPont). The preferred reaction is accomplished with about three equivalents of potassium peroxymonosulfate in a 50% aqueous solution of tetrahydrofuran.
The C2-methylene group can be derivatized to provide compounds of formula (I) or (II) by a variety of methods. Examples of suitable procedures for accomplishing the derivatization are shown below in Scheme 4. 
As illustrated in Scheme 4, the C2-methylene of compound 4 can be oxidized to the diol 5. The diol 5 can be selectively alkylated or acylated with a suitable reagent of the formula R8-X, wherein R8 is an alkyl, aryl, acyl or arylacyl group and X is a leaving group, for example, halogen, sulfonate, methanesulfonate, toluenesulfonate, or trifluoromethanesulfonate, in the presence of a base to obtain 6. A suitable base for the reaction is sodium hydride or sodium bis(trimethylsilyl) amide.
To directly modify the C2-position, a compound of formula 4 can be reacted with an organolithium or a Grignard reagent of the formula R9-M, wherein R9 is alkyl and M is a metal, in the presence of copper(I) reagent, for example copper(I) bromide, copper(I) iodide, copper(I) cyanide, and the like, to give the 1,4-addition product 7. Other nucleophiles are also suitable for the reaction. Examples of such nucleophiles include, but are not limited to, sodium enolate, allyl silane, allyl zinc, sodium malonate, sodium sulphonate, thiophenol, acetonitrile anion, sodium imidazole, and the like. Subsequent alkylation of compound 7 with a nitrogen electrophiles of the formula R10-X, wherein R10 is an electrophilic nitrogen group and X is a leaving group to give compound 8. Examples of electrophilic nitrogen reagents include but not limited to chloro amide (ClNH2), diphenylphosphoryl amide (Ph2P(O)ONH2), toluenesulfonylazide (TsN3), 2,4-dinitrophenylamine oxide((2,4-DNP)ONH2). In addition compound 7 can be treated with a base such as sodium hydride or potassium tert-butoxide followed by reacting with an electrophilic halide, represented by X1, to give compound 9.
Treatment of the C2-methylene of 4 with hydrogen peroxide affords an epoxide moiety of 10. Nucleophilic addition with a group R11 to the epoxide of 10 can afford a C2-alcohol 11.
The intermediate 4 can be hydrolyzed to the intermediate of formula (V) to provide an additional intermediate for further C2-derivatization. The intermediate of formula (V) can also be obtained from 2-norerythromycin in the manner described for Scheme 1. Further modifications of the C2-position are shown below in Scheme 5. 
As shown in Scheme 5, alkylation of the compound of formula (V) affords the compound 12 under alkylation conditions previously described for modifying the C2-methylene moiety. The C2-position of (V) can be treated with osmium tetroxide to obtain the C2-hydroxy of 13. The intermediate 13 can be further alkylated or acylated with a reagent of formula Rl4-X to obtain the compound 14.
In addition, the compound of formula (V) can be treated with a halogenating reagent in the present of a base to prepare compound 15. A suitable halogenating reagent is capable of replacing a hydrogen atom at the C2-position with a halogen atom. Various halogenating reagents can be used for the reaction. The preferred halogenating reagents are fluorinating reagents, for example N-fluorobenzenesulfonimide or (CF3SO2)2NF. Methods for replacing the C2-hydrogen with a halogen atom are also discussed in PCT Publication No. WO 99/21871, which is herein incorporated by reference.
Treating compound 15 with a halogenating reagent under the conditions described above affords a compound of formula 16.
Compounds 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and (V) are representative of C2-modified derivatives within the scope of formula (I). It will be readily apparent to one of skill in the art that the synthetic routes described above can be carried out with substitution of the substrate, reactants, or reagents to obtain compounds of formula (II). One of ordinary skill in the art will also recognize that other compounds within formula (I) and (II) can be synthesized by the substitution of the appropriate reactants and reagents in the syntheses shown in Schemes 3, 4 and 5.
6-O-alkenyl- and 6-O-alkynyl-substituted ketolide derivatives of erythromycin can be optionally coupled with an aromatic group to obtain compounds of formula (I) or (II), wherein R1 is C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl optionally substituted with a group R2, wherein R2 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, or Ar1-Ar2, wherein Ar1 and Ar2 are as previously defined.
A compound having 6xe2x80x94O-substitution 
for example, can be coupled with a suitable aromatic group by methods of transition metal-catalyzed coupling. Methods for coupling aryl groups to the 6-O-alkenyl and 6-O-alkynyl groups, particularly 6xe2x80x94O-allyl and 6xe2x80x94O-propargyl, respectively, of macrolide derivatives are described in U.S. Pat. No. 5,866,549 and U.S. patent application Ser. No. 09/270,497, which are herein incorporated by reference.
A suitable aromatic group can be provided by an aromatic halide or aromatic trifluoromethanesulfonate reagent. Examples of such reagents include, but are not limited to, an aryl halide, substituted aryl halide, heteroaryl halide, or substituted heteroaryl halide, or a bifunctionalized aryl or heteroaryl precursor group.
Reaction of the allyl-substituted derivatives with an aryl halide is performed in the presence of Pd(II) or Pd(0) catalysts with promoters such as phosphines, arsines, amines, and inorganic bases in polar, aprotic solvents; see Organic Reactions, 1982, 27, 345-390. Preferably, the promoters are selected from the group consisting of triphenylphosphine, triphenylarsine, pyridine and triethylamine, potassium carbonate, and cesium fluoride. The aprotic solvents are as previously defined such as dimethylformamide, dimethyl sulfoxide, dimethylethane, acetonitrile, tetrahydrofuran, or mixtures thereof. The reaction is accomplished at temperatures from about room temperature to about 150xc2x0 C., depending on the reagents chosen and the nature of the aryl halide.
The 6xe2x80x94O-propargyl groups can be derivatized under Sonagashira conditions by combining the alkyne derivative with an aryl halide in the presence of a phosphine promoter and Cu(I) optionally in the presence of an organic base. Preferably, the organic base is triethylamine. Summary of the procedures, reagents, and solvents for coupling terminal alkynes with aryl halides is described in Tetrahedron Lett., 1975, 50, 4467-4470.
The propargyl carbamate derivatives can be derivatized with borane-THF in aprotic solvents at temperatures from about xe2x88x9220xc2x0 C. to about room temperature to provide vinyl boronic acid derivatives. The vinyl boronic acid derivatives can be reacted under Suzuki conditions with aryl halide reagents, catalysts and promoters to provide allyl products similar to the Heck coupling reaction of the aryl halide as described above. A thorough discussion of Suzuki conditions is provided in Chemical Reviews, 1995, Vol. 95, No. 7, 2457-2483.
The Heck and Sonagashira conditions described above can also be used to couple aryl groups to allyl and propargyl groups at the C2-position of the macrolide. For example, a C2-allyl group can be reacted with an aryl halide in the presence of Pd(II) or Pd(0) catalysts with a promoter to afford a compound wherein R3 is xe2x80x94CH2Cxe2x95x90CHxe2x80x94R2, wherein R2 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, or Ar1-Ar2. Likewise, a C2-propargyl group can be treated under Sonagashira conditions with an aryl halide in the presence of a phosphine promoter and Cu(I) optionally in the presence of an organic base to give compounds wherein R3 is a group xe2x80x94CH2Cxe2x89xa1Cxe2x80x94R2, and R2 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, or Ar1-Ar2.
It will be readily apparent to one of ordinary skill other compounds of formulae (I) and (II) can be synthesized by substitution of the appropriate reactants and agents in the syntheses described. It will also be apparent to one skilled in the art that the selective protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, depending on the nature of the substrate compound and the substituents.
Representative compounds of the present invention were assayed in vitro for antibacterial activity as follows: twelve petri dishes containing successive aqueous dilutions of the test compound mixed with 10 mL of sterilized Brain Heart Infusion (BHI) agar (Difco 0418-01-5) were prepared. Each plate was inoculated with 1:100 (or 1:10 for slow-growing strains, such as Micrococcus and Streptococcus) dilutions of up to 32 different microorganisms, using a Steers replicator block. The inoculated plates were incubated at 35-37xc2x0 C. for 20-24 hours. In addition, a control plate using BHI agar with no test compound was prepared and incubated at the beginning and end of each test.
A plate containing erythromycin A was also prepared to provide test-to-test comparability. Erythromycin A has susceptibility patterns for the organisms being tested and belongs to the same antibiotic class as the test compounds.
After incubation, each plate was visually inspected. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of drug yielding no growth, a slight haze, or sparsely isolated colonies on the inoculum spot as compared to the growth control. The results of this assay, shown below in Table 1, demonstrate the antibacterial activity of the compounds of the invention.
The compounds and processes of the invention will be better understood in connection with the Examples, which are intended as an illustration of and not a limitation upon the scope of the invention as defined in the appended claims.